We have ectopically expressed transcription factor ETS! in two different highly tumorigenic human colon cancer cell lines, DLD-1 and HCT116, that do not express endogenous ETS1 protein and have obtained several independent clones. The expression of wild-type ETS1 protein in these colon cancer cells reverses the transformed phenotype and tumorigenicity in a dose-dependent manner. By contrast, expression in DLD-1 cells of a variant form of ETS1, lacking transcriptional activity, did not alter the tumorigenic properties of the cells, suggesting that the reduction in tumorigenicity in these clones was specific for the wild-type ETS1 gene products. DLD-1 wild-type ETS1 transfectants grow much slower in serum-free media than DLD-1 cells expressing mutant ETS1 proteins lacking transcriptional activities. Furthermore, DLD-1 wild-type ETS1 transfectants remain longer in G0/G1 stage of the cell cycle than DLD-1 mutant ETS1 transfectants. These results suggest that ETS1 protein under appropriate conditions may interfere with growth of colon cancer cells. To identify functional domains of ETS1 involved in tumor suppressor function, we have generated variant forms of ETS1 lacking either transcriptional activities or DNA binding activities. Experiments are in progress to express mutant ETS1 proteins in colon, breast and prostate cancer cells as well as to identify "minimum region of ETS1" responsible for suppression of tumorigenicity of colon cancer cells.